Nu-aminomethyltetracycline derivatives



3,159,631 N-AMINOMETHYLTEIRACYCLINE DEREVATIVES Maxwell Gordon, ElkinsPark, and Elaine M. Sutton,

Philadelphia, Pa., assignors to Smith Kline & French Laboratories,Philadelphia, Pa, a corporation of Pennsylvania No Drawing. Filed Aug.30, 1960, Ser. No. 52,758

1 Claim. (Cl. 260-268) This invention relates to novelN-aminomethyltetracycline derivatives having improved therapeuticproperties.

' More specifically, the tetracycline derivatives of this invention havea broad spectrum of potent antimicrobial activity and, in addition, arecharacterized by greatly enhanced .water solubility at all pH levelsthereby providing increased speed and efficiency of antibioticabsorption. The compounds of this invention are active, for example,against the followingtype's of organisms: Clostridium, Corynebacterium,Diplococci, Escherichia, Hemophilis, Klebsiella, Micrococci, Neisseria,Pasteurella, Salmonella, Shigella and streptococci.

The N-aminomethyltetnacyclines of this invention are represented by thefollowing structural formula:

FORMULA l CH3 CH3 R1 l (R1 when R is hydrogen;

R is hydrogen;

R is hydroxy;

R is methyl;

R is trifiuoromethylsulfonyl; and R is N-hydroxyalkylpiperazinyl.

This invention also includes pharmaceutically accept able salts of theabove defined bases formed with nontoxic organic and inorganic acids.Such salts-are easily prepared by methods known to the art. The base isreacted with either the calculatedlamount of organic or United StatesPatent 0 namic, citraconic, asparti'c, stearic, palmitic, itaconic,

glycolic, p-aminobenzoic, glutamic, benzene sulfonic and theophyllineacetic acids as well as with the S-halotheophyllines, for example,8-bromotheophylline. Exemplary of such inorganic salts are those withhydrochloric, hydrobromic, sulfuric; sulfamic, phosphoric and nitricacids.

The term alkyl Where used herein in combination 3,159,631 Patented Dec.1,1964

with other terms denotes hydrocarbon chains of from 2-4 carbon atoms,preferably 2 carbon atoms.

Our novel compounds are prepared by a Mannich reaction of a tetracyclinecompound with formaldehyde and an amine according to the followingprocedure:

when R are as defined hereabove.

The tetracycline starting material is reacted with a least one molarequivalent of formaldehyde and of the amine, prefer-ably about 1.05-1'2.molar equivalents of formaldehyde and about 1.1-2.0 molar equivalents ofthe amine. The reaction is preferably carried out in an alcohol solventsuch as ethyl, isopropyl, isoamyl or preferably, t-butyl alcohol, atelevated temperature such as fromabout -135 C. conveniently at thereflux temperature of the solvent. Preferably the reactants are stirredat room temperature for about 10-60 minutes, then heated at refluxtemperature for about 10 minutes to four hours, preferably 15-30minutes.

Example 1 A mixture of 22.2 g. of tetracycline and 33.5 g. oftrifiuoromethylsulfonic acid is stirred at 0 C. for 30 minutes. The coldsolution is poured into ether. The precipitate is filtered off anddissolved in Water. The aqueous solution is neutralized, chilled andfiltered. Fractional crystallization of the solid material from ethanolgives 7-trifluoromethylsulfonyltetracycline.

To a suspension of 14.2 g. of 7-trifluoromethylsulfonyltetracycline inml. of t-butyl alcohol is added 2.3 g. of 37% formaldehyde and 3.9 g. ofN-hydroxyethylpiperazine. The resulting mixture is refluxed for 30minutes, then Worked up as in Example 1 to give7-trifluoromethylsulfonyl N [1-(4 hydroxyethyl)piperazinylmethyl]tetracycline.

What is claimed is: A chemical compound having the structural formula:

so, CH OH CH CH Nomcnron (References on following page) 3 4 ReferencesCited in the file of this patent 808,701 Great Britain Feb. 11, 1959UNITED STATES PATENTS 808,702 Great Britain Feb. 11, 1959 809 585 GreatBritain Feb. 25 1959 2,997,471 Cheney et al. Aug. 22, 1961 3,029,284Gordon Apr. 10 1962 5 3169/57 Union of South Africa July 22, 19583,063,996 Gordon Nov. 13, 1962 OTHER REFERENCES 3 080 288 Tonelli et a1Mar 5 1963 t McCormick et 211.: Journal American Chemical So- 3,081,346Stephens et a1 Mar. 12, 1963 ciety v01. 79, pages 456143 (1957).

, FOREIGN PATENTS Stephens at 211.: Journal American Chemical Society,748,724 Great Britain May 9, 1956 10 pages 532425 785,047 Great BritainOct. 23, 1957 Siedel et al.: Munchenen Medizinische Wochen- 1,044,806Germany Nov. 27, 1958 schrift, vol. 100, pages 661-662 (April 1958).

